Epigenetic mediation may explain intergenerational associations between maternal lifestyle and birth weight of offsprings - Findings from the NorthPop prospective birth cohort

BackgroundEpigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease (DOHAD) hypothesis. ObjectivesTo assess the association of maternal lifestyle with offsprings birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort. MethodsA three-step analytic pipeline was applied. In 722 mother-child pairs, overall associations between 10 maternal lifestyle factors and the offsprings standardized birth weight were first evaluated by multiple linear regression. Three high dimensional mediation methods (HDMA, HIMA, and HIMA2) were then applied on the beta methylation matrix to identify candidate CpG mediators in cord blood driving the significant overall associations. Finally, robust- and ordinary least squares-regression-based classical mediation, including single- and multiple-(parallel and serial) mediator models were assessed. ResultsGestational weight gain (GWG) ({beta}-adj = 0.03; p = 2x10-5) and maternal BMI at the beginning of pregnancy ({beta}-adj = 0.036; p = 1x10-4) were significantly associated with the offsprings standardized birth weight. High dimensional mediation analyses identified pooled sets of four (cg19242268; cg08461903; cg14798382; cg21516291) and five (cg17040807; cg19242268; cg26552621; cg04457572; cg06457011) candidate CpG mediators related to GWG and BMI at the beginning of pregnancy, respectively. For both exposures, classical mediation analyses revealed a range of significant single- and multiple (both serial and parallel) mediator models via both robust- and OLS-regression based approaches. These indicated the likely presence of individual-, causally linked multiple-, and causally independent multiple mediatory pathways underlying the two significant overall associations. ConclusionsOur findings support the hypothesis that neonatal health effects related to maternal lifestyle may be partly mediated by epigenetic alterations. Findings also suggest the possible involvement of multiple DNA methylation sites via various mediatory pathways.